Nails are unique structures found on the fingers and toes. The nail apparatus consists of a nail plate and its associated soft tissue (the proximal nail fold, the matrix, the nail bed, and the hyponychium). In common lay usage the terms “fingernail” and “toenail” refer to the nail plate.
The nail plate is a unique skin structure. It consists mostly of highly filamentous proteins, known as keratin, embedded in an amorphous matrix. The nail plate differs from ordinary skin in many ways. Besides being much harder than ordinary skin, the nail plate also has a much lower lipid content, higher keratin content, more disulfide bonds and a much lower ability to absorb water. Because of the unique structure of nails, they present unique problems for the clinician who treats their disorders.
Onychomycosis is a frequently occurring disorder of the nails. It is caused by an infection of the nail plate and associated structures by fungi or yeasts. Most often, onychomycosis is caused by an infection of dermatophyte fungi of the genus Tinea. Onychomycosis results in a thickening and discoloration of the nails which can become breakable.
Onychomycosis is rarely, if ever, life threatening. It can be painful and is usually very unsightly and the cause of much embarrassment for the patient, especially when the fingernails are involved.
There are number of treatments for onychomycosis, none of which are highly effective.
A ciclopirox 8% nail lacquer (similar to nail polish) is sometimes used to treat onychomycosis. Sold under the brand Penlac, this product must be applied to the affected nails every day for almost a year. It results in complete clinical and mycological clearance in less than a quarter of cases.
Oral terbinafine hydrochloride is sold under the brand Lamisil and is used to treat onychomycosis. Terbinafine must be taken every day for three months in order to have success in treating onychomycosis of the toenail. Because it is administered orally, terbinafine therapy for onychomycosis is subject to a variety of adverse events unrelated to the treatment site, including gastrointestinal disorders, rashes, disruption of the sense of taste, and liver disorders. A complete course of treatment with terbinafine results in complete clearance in only a minority of cases.
In the many cases that are not responsive to topical or systemic drug therapy, the only remaining treatment for onychomycosis is the surgical or chemical removal of the nail plate which exposes the nail bed. Topical antifungals are then applied to the exposed nail bed while the nail plate is allowed to regrow, a process which takes about a year in the case of toenails.
Photodynamic therapy (PDT) is an established therapeutic method for certain disorders. PDT is characterized by the use of (1) a phototherapeutic agent and (2) light. The phototherapeutic agent is applied or provided to the tissue or organ of interest. The light is used to cause a photo-reaction (such as photoexcitation) in either the phototherapeutic agent, or in a metabolite of the phototherapeutic agent, or in a compound produced in response to the presence of the phototherapeutic agent (the activation reaction). This reaction results in a therapeutic effect.
Early phototherapeutic agents included porphyrins such as hematoporphyrin IX, hematoporphyrin derivative, or other such molecules, including Photofrin II.
The pioneering work of Kennedy & Pottier resulted in the discovery of the use of aminolevulinic acid (ALA) as a phototherapeutic agent. ALA is a precursor to a naturally occurring molecule—protoporphyrin IX. Exposing skin to light activates protoporphyrin IX in the skin. That is, the light excites or causes a reaction in the protoporphyrin IX molecule that results in the formation of reactive free radicals. Naturally occurring protoporphyrin IX can be activated by exposure to light, but occurs in quantities too small to cause any serious effect in normal tissue. By administering exogenous ALA, cells and tissues can be caused to produce greatly increased amounts of protoporphyrin IX. The resulting high concentrations of protoporphyrin IX can result in the generation of fatal quantifies of free radicals in the target cells/tissue when protoporphyrin IX is activated by exposure to light.
Kennedy & Pottier found that ALA-induced production of protoporphyrin IX made it possible to use PDT in the treatment of several disorders of metabolically active tissues. This technology has been used in the successful commercial product Levulan®, produced by Dusa Pharmaceuticals, and which has been approved by the U.S. FDA for the treatment of actinic keratoses.
Kennedy and his co-workers believed that ALA-based PDT could be used to treat acne, although they did not report any clinical resolution of acne by this method. See, U.S. Pat. No. 5,955,490. Also, they reported that the ability of light to specifically excite protoporphyrin IX in acne lesions disappeared within 24 hours.
Other workers in this field tried to employ ALA-based PDT in the treatment of acne. See, U.S. Pat. No. 6,897,238 to Anderson. Anderson used ALA based PDT to treat acne in a small group of patients and taught that light must be applied to the skin within one to 12 hours after application of ALA to the skin containing acne lesions, preferably about three hours after application of the ALA.
Anderson's use of a 1 to 12 hour waiting period, and preferably a three hour waiting period between ALA application and exposure to light was consistent with what was by then the generally accepted timeline of ALA metabolism and protoporphyrin IX production. Research by Kennedy & Pottier showed that ALA was metabolized in mouse skin to result in peak protoporphyrin IX concentration in about six hours, with protoporphyrin levels returning to near pretreatment baseline in about 18 hours. Pottier et al, Photochemistry and Photobiology, Vol. 44, No. 5, pp. 679-87 (1986).
ALA-based PDT was thought to have an ability to treat dermatophytic infections. Kennedy and Pottier reported the use of PLA-based PDT to treat onychomycosis of the toenail in U.S. Pat. No. 6,710,066. ALA was applied to the nail and the nail was exposed to photoactivating light four hours later. While they reported success in resolving the fungal infection, they also reported that ALA-based PDT caused redness and edema (swelling). Subsequent experience with this technique has shown that the edema caused by ALA-based PDT treatment of onychomycosis can be painful and severe. In some cases the swelling is so great that it restricts blood flow to the toe causing gangrene, which requires amputation of the toe. Lowering the dosage of ALA to avoid dangerous swelling of the toe and restriction of the blood flow results in the loss of effectiveness of the treatment.
There remains a great need for a highly effective and safe treatment of onychomycosis.